IMPACT OF DIFFERENT FLUOROURACIL BIOCHEMICAL MODULATORS ON CELLULAR DIHYDROPYRIMIDINE DEHYDROGENASE

In attempts to increase fluorouracil (FU) activity by pharmacomodulati on, most attention has been paid to FU activation pathways without con sideration of the presence and possible role of FU catabolism in the t arget tumoral cell itself. The first step in the catabolism of FU is h ydrogenation by the enzyme dihydropyrimidine dehydrogenase (DPD). The purpose of the present study was to test the DPD-inhibitory effects of several agents whose use as FU biomodulators has been clinically esta blished: cisplatin, hydroxyurea, dipyridamole, and allopurinol. Five c ancer cell lines of human origin were used. Dipyridamole and hydroxyur ea were the only modulators for which an augmentation in FU cell-growt h inhibition (MTT test) was clearly evident for the whole panel of cel l lines investigated (P < 1.10(-4) and P = 0.005, respectively). With dipyridamole the efficacy of FU was multiplied by a factor of around 5 . Allopurinol and cisplatin had no obvious effect on cellular DPD acti vity (biochemical method). For dipyridamole and hydroxyurea, DPD activ ity showed a more or less marked concentration-related inhibition acco rding to the cell line tested. Only dipyridamole produced reductions i n FU IC50 values (50% growth-inhibitory concentrations), i.e., potenti ation of FU cytotoxicity, that were significantly related to inhibitio n of cellular DPD activity. This DPD-mediated interaction between dipy ridamole and FU is a new finding that could be important for a better understanding of FU-dipyridamole combination chemotherapy.